Mechanism of Crosstalk between m6A Modification and Epigenetic Regulation
Crosstalk ID
M6ACROT03178
[1]
m6A modification EED EED YTHDC1 : m6A sites Indirect Inhibition Histone modification H3K27me3 EZH2 Downstream Gene
m6A Modification:
m6A Regulator YTH domain-containing protein 1 (YTHDC1) READER
m6A Target Polycomb protein EED (EED)
Epigenetic Regulation that have Cross-talk with This m6A Modification:
Epigenetic Regulation Type Histone modification (HistMod)
Epigenetic Regulator Histone-lysine N-methyltransferase EZH2 (EZH2) WRITER View Details
Regulated Target Histone H3 lysine 27 trimethylation (H3K27me3) View Details
Crosstalk Relationship m6A  →  Histone modification Inhibition
Crosstalk Mechanism m6A modification indirectly regulates histone modification through downstream signaling pathways
Crosstalk Summary METTL3 deletion in the endometrium alters mRNA m6A methylation via Polycomb protein EED (EED) interaction. This reduces m6A recognized by YTHDC1, which recruits Eed to suppress EZH2-mediated Histone H3 lysine 27 trimethylation (H3K27me3) modification co-transcriptionally. The reduction of H3K27me3 disrupts chromatin accessibility and impairs transcription of genes critical for endometrial receptivity. Collectively, these results shed light on a Mettl3-Eed-m6A-Ythdc1 axis that links m6A and histone modification in regulating local chromatin state and gene expression, advancing our understanding of the epigenetic crosstalk between RNA and DNA modification in infertility disease.
Full List of Potential Compound(s) Related to This m6A-centered Crosstalk
Histone-lysine N-methyltransferase EZH2 (EZH2) 74 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name Tazemetostat Approved [2]
Synonyms
EPZ-6438; 1403254-99-8; EPZ6438; UNII-Q40W93WPE1; N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide; Q40W93WPE1; EPZ 6438; E7438; (1,1'-Biphenyl)-3-carboxamide, N-((1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(4-morpholinylmethyl)-
    Click to Show/Hide
MOA Inhibitor
Activity Ki = 2.5 nM
External Link
 Compound Name DS-3201b Phase 2 [3]
Synonyms
Valemetostat; 1809336-39-7; UNII-60RD0234VE; 60RD0234VE; 1809336-39-7 (free base); DS-3201; (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide; Valemetostat 2HCl; Valemetostat [INN]; Valemetostat (DS-3201); CHEMBL4597193; EZH1/2 inhibitor DS-3201; SCHEMBL18393626; SCHEMBL18393627; SCHEMBL18639210; EX-A3423; DS3201; NSC813381; s8926; NSC-813381; HY-109108; CS-0039740; D11551
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MOA Inhibitor
External Link
 Compound Name CPI-1205 Phase 1/2 [4]
Synonyms
HPODOLXTMDHLLC-QGZVFWFLSA-N; 1621862-70-1; UNII-455J2479FY; CPI1205; CPI 1205; 455J2479FY; (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide; GTPL9115; SCHEMBL17329268; MolPort-044-560-382; KS-000006BA; EX-A1068; s8353; AKOS030628484; ZINC220982768; CS-7648; compound 13 [PMID: 27739677]; HY-100021; J3.556.402K; N-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-2-methyl-1-[(1R)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-
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MOA Inhibitor
External Link
 Compound Name SHR2554 Phase 1/2 [5]
MOA Inhibitor
External Link
 Compound Name CPI-0209 Phase 1/2 [6]
MOA Inhibitor
External Link
 Compound Name GSK2816126 Phase 1 [7]
Synonyms
GSK 126; GSK-126
    Click to Show/Hide
MOA Modulator
Activity Ki = 0.5 nM
External Link
 Compound Name PF-06821497 Phase 1 [8]
Synonyms
UNII-S4L4MM20B6; S4L4MM20B6; CHEMBL4080228; PF06821497; 1844849-10-0; 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one; SCHEMBL17330426; GTPL10516; BDBM50246967; NSC800019; DB14799; HY-101571A; NSC-800019; compound 23a [PMID: 29211475]; CS-0092626; Q29209799; 1(2H)-Isoquinolinone, 5,8-dichloro-2-((1,2-dihydro-4-methoxy-6-methyl-2-oxo-3-pyridinyl)methyl)-3,4-dihydro-7-((R)-methoxy-3-oxetanylmethyl)-; 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1-one; CJD
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name DS-3201 Phase 1 [4]
Synonyms
QTGYNKYZRZATJB-UHFFFAOYSA-N; 701899-63-0; 2-(2-(2-Methyl-1H-imidazol-5-yl)ethyl)isoindoline-1,3-dione; 2-(2-(2-Methyl-1H-imidazol-5-yl)-ethyl)isoindoline-1,3-dione; SCHEMBL7743461; MolPort-035-945-474; MolPort-035-690-353; ZINC98086069; AKOS024459002; AKOS024262663; MCULE-2708350770; FCH4077443; AK158834; AX8292467; ST2403812; 2-[2-(2-methyl-1H-imidazol-5-yl)ethyl]-2,3-dihydro-1H-isoindole-1,3-dione
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name HH2853 Phase 1 [9]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-33 Patented [10]
MOA Inhibitor
Activity IC50 = 100 nM
External Link
 Compound Name PMID28394193-Compound-Figure3bI Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-35 Patented [10]
MOA Inhibitor
Activity IC50 = 10 nM
External Link
 Compound Name PMID28394193-Compound-54 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-24 Patented [10]
MOA Inhibitor
Activity IC50 < 1000 nM
External Link
 Compound Name PMID28394193-Compound-27 Patented [10]
MOA Inhibitor
Activity IC50 < 1000 nM
External Link
 Compound Name PMID28394193-Compound-25 Patented [10]
MOA Inhibitor
Activity IC50 < 1000 nM
External Link
 Compound Name PMID28394193-Compound-50 Patented [10]
MOA Inhibitor
Activity IC50 > 1 nM; IC50 < 2 nM; Ki > 0.01 nM; Ki < 0.04 nM
External Link
 Compound Name PMID28394193-Compound-47 Patented [10]
MOA Inhibitor
Activity IC50 = 2 nM; Ki < 1 nM
External Link
 Compound Name PMID28394193-Compound-21 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-41 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-53 Patented [10]
MOA Inhibitor
Activity IC50 = 80 nM
External Link
 Compound Name PMID28394193-Compound-Figure5aVIII Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-38 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-51 Patented [10]
MOA Inhibitor
Activity IC50 > 1 nM; IC50 < 2 nM; Ki > 0.01 nM; Ki < 0.04 nM
External Link
 Compound Name PMID28394193-Compound-31 Patented [10]
MOA Inhibitor
Activity IC50 = 20 nM
External Link
 Compound Name PMID28394193-Compound-42 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-15 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-52 Patented [10]
MOA Inhibitor
Activity IC50 > 1 nM; IC50 < 2 nM; Ki > 0.01 nM; Ki < 0.04 nM
External Link
 Compound Name PMID28394193-Compound-32 Patented [10]
MOA Inhibitor
Activity IC50 = 500 nM
External Link
 Compound Name PMID28394193-Compound-23 Patented [10]
MOA Inhibitor
Activity IC50 < 1000 nM
External Link
 Compound Name PMID28394193-Compound-29 Patented [10]
MOA Inhibitor
Activity IC50 = 100 nM
External Link
 Compound Name PMID28394193-Compound-30 Patented [10]
MOA Inhibitor
Activity IC50 = 16 nM
External Link
 Compound Name PMID28394193-Compound-39 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-49 Patented [10]
MOA Inhibitor
Activity IC50 > 1 nM; IC50 < 2 nM; Ki > 0.01 nM; Ki < 0.04 nM
External Link
 Compound Name PMID28394193-Compound-43 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-40 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-Figure3bIII Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-36 Patented [10]
MOA Inhibitor
Activity IC50 = 316 nM
External Link
 Compound Name PMID28394193-Compound-28 Patented [10]
MOA Inhibitor
Activity IC50 = 32 nM
External Link
 Compound Name PMID28394193-Compound-22 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-18 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-16 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-44 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-20 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-19 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-37 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-Figure3bII Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-26 Patented [10]
MOA Inhibitor
Activity IC50 < 1000 nM
External Link
 Compound Name PMID28394193-Compound-17 Patented [10]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-34 Patented [10]
MOA Inhibitor
Activity IC50 = 100 nM
External Link
 Compound Name PMID28394193-Compound-56 Patented [10]
MOA Inhibitor
Activity IC50 = 0.93 nM
External Link
 Compound Name PMID28394193-Compound-46 Patented [10]
MOA Inhibitor
Activity IC50 = 5 nM
External Link
 Compound Name PMID28394193-Compound-57 Patented [10]
MOA Inhibitor
Activity IC50 = 6.45 nM
External Link
 Compound Name PMID28394193-Compound-14 Patented [10]
MOA Inhibitor
Activity IC50 = 21900 nM
External Link
 Compound Name PMID28394193-Compound-12 Patented [10]
MOA Inhibitor
Activity IC50 < 10 nM
External Link
 Compound Name PMID26882240-Compound-1 Patented [11]
MOA Inhibitor
External Link
 Compound Name PMID28394193-Compound-55 Patented [10]
MOA Inhibitor
Activity IC50 = 8.13 nM
External Link
 Compound Name PMID28394193-Compound-45 Patented [10]
MOA Inhibitor
Activity IC50 = 168000 nM
External Link
 Compound Name PMID28394193-Compound-13 Patented [10]
MOA Inhibitor
Activity IC50 = 1470 nM
External Link
 Compound Name EPZ005687 Investigative [12]
Synonyms
EPZ-005687; EPZ 005687
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name EI1 Investigative [13]
Synonyms
KB-145943
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MOA Inhibitor
External Link
 Compound Name UNC1999 Investigative [14]
Synonyms
UNC 1999; UNC-1999
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name MS1943 Investigative [5]
Synonyms
2225938-17-8; SCHEMBL21271666; EX-A3962; s8918; HY-133129; CS-0112146; 6-(6-(4-(2-(2-((3r,5r,7r)-adamantan-1-yl)acetamido)ethyl)piperazin-1-yl)pyridin-3-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide; 6-(6-(4-(2-(2-(Adamantan-1-yl)acetamido)ethyl)piperazin-1-yl)pyridin-3-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide
    Click to Show/Hide
MOA Degrader
External Link
 Compound Name GSK343 Investigative [15]
Synonyms
compound 6 [PMID 24900432]; GSK 343
    Click to Show/Hide
MOA Inhibitor
Activity IC50 = 174 nM
External Link
 Compound Name PMID28394193-Compound-11 Patented [16]
External Link
 Compound Name PMID28394193-Compound-10 Patented [16]
External Link
 Compound Name PMID28394193-Compound-14 Patented [10]
MOA Inhibitor
Activity IC50 = 21900 nM
External Link
 Compound Name PMID28394193-Compound-12 Patented [10]
MOA Inhibitor
Activity IC50 < 10 nM
External Link
 Compound Name PMID28394193-Compound-13 Patented [10]
MOA Inhibitor
Activity IC50 = 1470 nM
External Link
 Compound Name PMID28394193-Compound-56 Patented [10]
MOA Inhibitor
Activity IC50 = 0.93 nM
External Link
 Compound Name PMID28394193-Compound-46 Patented [10]
MOA Inhibitor
Activity IC50 = 5 nM
External Link
 Compound Name PMID28394193-Compound-57 Patented [10]
MOA Inhibitor
Activity IC50 = 6.45 nM
External Link
 Compound Name PMID28394193-Compound-55 Patented [10]
MOA Inhibitor
Activity IC50 = 8.13 nM
External Link
 Compound Name PMID28394193-Compound-45 Patented [10]
MOA Inhibitor
Activity IC50 = 168000 nM
External Link
Polycomb protein EED (EED) 3 Compound(s) Regulating the Target Click to Show/Hide the Full List
 Compound Name MAK683 Phase 1/2 [4]
Synonyms
XLIBABIFOBYHSV-UHFFFAOYSA-N; EED inhibitor-1; 1951408-58-4; MAK-683; N-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine; N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine; SCHEMBL17841485; EX-A1723; BCP29116; ACN-053195; CS-8054; AC-30344; HY-103663
    Click to Show/Hide
MOA Inhibitor
External Link
 Compound Name ORIC-944 Phase 1 [17]
MOA Inhibitor
External Link
 Compound Name A-395 Investigative [18]
Synonyms
CHEMBL4104741; (3R,4S)-1-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-N,N-dimethyl-4-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrrolidin-3-amine; GTPL9525; SCHEMBL19549392; BDBM223987; BDBM50241662; A-395 hydrochloride, >=98% (HPLC); HY-101512; CS-0021615; J3.609.234C; A-395 (5); A392089148-72-9; (3R,4S)-1-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-N,N-dimethyl-4-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]pyrrolidin-3-amine; 2089148-71-8; rac-(3R,4S)-1-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-N,N-dimethyl-4-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrrolidin-3-amine (4); rel-(3R,4S)-1-(7-Fluoro-2,3-dihydro-1H-inden-1-yl)-N,N-dimethyl-4-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)pyrrolidin-3-amine
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MOA Inhibitor
External Link
References
Ref 1 Mettl3/Eed/Ythdc1 regulatory axis controls endometrial receptivity and function. Commun Biol. 2025 Feb 11;8(1):215. doi: 10.1038/s42003-025-07667-y.
Ref 2 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
Ref 3 Development of new agents for peripheral T-cell lymphoma. Expert Opin Biol Ther. 2019 Mar;19(3):197-209. doi: 10.1080/14712598.2019.1572746. Epub 2019 Jan 29.
Ref 4 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Ref 5 Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease. Nat Rev Drug Discov. 2021 Apr;20(4):265-286. doi: 10.1038/s41573-020-00108-x. Epub 2021 Jan 19.
Ref 6 ClinicalTrials.gov (NCT04104776) A Study of CPI-0209 in Patients With Advanced Tumors. U.S. National Institutes of Health.
Ref 7 National Cancer Institute Drug Dictionary (drug id 756211).
Ref 8 Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497). J Med Chem. 2018 Feb 8;61(3):650-665. doi: 10.1021/acs.jmedchem.7b01375. Epub 2017 Dec 27.
Ref 9 Clinical pipeline report, company report or official report of HaiHe Biopharma.
Ref 10 EZH2 inhibitors: a patent review (2014-2016). Expert Opin Ther Pat. 2017 Jul;27(7):797-813. doi: 10.1080/13543776.2017.1316976. Epub 2017 Apr 20.
Ref 11 Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015). Expert Opin Ther Pat. 2016;26(3):309-22. doi: 10.1517/13543776.2016.1146252. Epub 2016 Feb 16.
Ref 12 A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012 Nov;8(11):890-6. doi: 10.1038/nchembio.1084. Epub 2012 Sep 30.
Ref 13 Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21360-5. doi: 10.1073/pnas.1210371110. Epub 2012 Dec 10.
Ref 14 An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324-34. doi: 10.1021/cb400133j. Epub 2013 Apr 24.
Ref 15 Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med Chem Lett. 2012 Oct 19;3(12):1091-6. doi: 10.1021/ml3003346. eCollection 2012 Dec 13.
Ref 16 TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751.
Ref 17 Clinical pipeline report, company report or official report of ORIC Pharmaceuticals
Ref 18 The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol. 2017 Apr;13(4):389-395.